(1). Field of Invention
This invention relates to antifungal nail lacquer compositions and to the treatment of onychomycoses or other fungal infestations affecting toe nails or finger nails using the nail lacquer composition. More particularly, the invention relates to antifungal nail lacquers which when applied to nails form strongly adherent, water-resistant, clear films; and to the method for treating or preventing fungal infestations of animal nails by applying the antifungal composition to the infected nail or to the fungal susceptible nail.
(2). State of the Prior Art
Fungal infection of the nails, commonly referred to as onychomycosis, is most frequently caused by dermatophytes but also can be caused by molds and Candida. Mixed infections also occur. Onychomycosis includes dermatophyte infection of the nail plate and includes infection of nails by any fungus, including yeast or molds. Thus, for example, onychomycosis serves as a reservoir for dermatophytes and contributes to treatment failure and recurrence of tinea pedis.
Most common causes of tinea unguium are Trichophyton rubrum (most frequent), T. mentagrophytes, and Epidermophyton floccusum. Onychomycosis due to nondermatophytes is usually caused by Candida species.
Nail lacquers for the treatment of onychomycoses and similar fungal infections affecting nails (toe nails and/or finger nails) of humans, in particular, or other animals, are known. Representative examples are described in the patent literature, of which the following U.S. Pat. Nos. can be mentioned: 4,957,730 (1-hydroxy-2-pyridone in water-insoluble film-former); 5,120,530 (amorolfine in quaternary ammonium acrylic copolymer); 5,264,206 (tioconazole, econazole, oxiconazole, miconazole, tolnaftate, naftifine hydrochloride, in water-insoluble film-former); 5,346,692 (with urea and dibutyl phthalate plasticizer); 5,487,776 (griseofulvin as colloidal suspension).
Other U.S. Pat. Nos. which relate to antifungal products include, for example, 4,636,520 (combination of imidazole and pyrrolnitrin); 5,002,938 (gel, combination of imidazole and 17-ester corticosteroid antiinflammatory agent); 5,110,809 (antifungal gel plus steroid); 5,219,877 (gel product with imidazole antifungal optionally with steroidal antiinflammatory, in a vehicle system that includes lauryl alcohol); 5,391,367 (aqueous alcoholic gel with tioconazole); 5,464,610 (salicylic acid plaster); 5,696,105 (mometasone furoate).
Effectiveness of nail lacquers as a delivery vehicle for topically administering the antifungal agent amorolfine is described by Jean-Paul L. Marty, J. of the European Academy of Dermatology and Venereology, 4(Suppl. 1), pp.S17-S21 (1995). As described by the author, the film-generating solution as the lacquer base for the active principle basically consists of volatile solvent (ethanol, ethyl/butyl/methyl acetate, methylene chloride, methyl ethyl ketone, isopropanol), and a non-water-soluble polymer (methacrylic acid copolymers, vinyl polymers) which leaves a thin continuous film following evaporation of the solvent. Plasticizers (triacetin, dibutyl phthalate) impart sufficient mechanical flexibility to prevent flaking and removal. Marty further notes the similarity of the film-generating solution to the nail lacquers used in cosmetics.
It is further explained that the specific aims addressed in formulating the film-generating solution of the anti-fungal nail lacquer include obtaining maximal affinity of the active principle to the nail keratin and obtaining the highest possible thermodynamic activity compatible with maintaining the active principle in true or supersaturated solution.
Differences in diffusion characteristics between nail and skin are also discussed in the Marty article. The nail structure is characterized as a water-gel in which water facilitates diffusion of at least polar compounds. In contrast, the skin tends to more readily facilitate diffusion of lipophilic, non-polar molecules, through the extracellular lipids of the stratum corneum. Thus, since the absolute transmission of water vapor through nails is about 10 times that through skin, and since nails are approximately 100 times as thick as stratum corneum, the permeability of nails to water vapor is about 1000 times greater.
Therefore, Marty reports that "excipients developed for use on skin are thus inappropriate for releasing active principles on the nail, as shown by the inefficacy of diffusion promoters such as DMSO" (citing Walters K A, Penetration of chemicals into, and through, the nail plate. Pharm Int. 1985; April, p. 85-89).
It has also been suggested in the literature (Mast, "Nail Products". . . ) that "[a]s a working hypothesis, it should be assumed that nails are, in general, quite permeable to polar and semipolar low molecular weight chemicals." See also, Walters K A and Flynn G L, "Permeability characteristics of the human nail plate" Intl J. of Cosmetic Science, 5, 231-246 (1983) for a review of the structure and characteristics of the nail and a discussion of permeation through the nail plate of various chemicals and permeation coefficients of C.sub.1 -C.sub.12 -alcohols.
These authors conclude, on the basis of the accumulated data that in connection with the successful formulation of drugs used in the treatment of nail infections, "that solvents with proven efficacy as skin `penetration enhancers` show little promise as enhancers of nail plate permeability" (citing to Walters, K A and Flynn G L, J. Pharm. Pharmac. 33 6P (1981) and Kligman, A M J. Amm. Med. Ass. 193 796-804 (1965).
Nevertheless, there remains a need for more effective and more durable (longer lasting) nail lacquer formulations which incorporate an antifungal agent.
There also remains a need for an antifungal nail lacquer formulation which provides clear and glossy films which are capable of resisting multiple washings.
It is also known in the art, as indicated by several of the patent documents discussed above, that the overall effectiveness of antimycotic products for treating fungal infections of the skin may often be improved by combining the antifungal agent with a steroidal antiinflammatory agent. To date however such combination products have not been formulated into a lacquer type product for the treatment of onychomycosis but, rather, have been limited to gels, lotions, creams and other topically applied solutions.